Regulation of amyloid-beta clearance by the small GTPase Arf6 and the phospholipid kinase PIP5K

小 GTP 酶 Arf6 和磷脂激酶 PIP5K 对淀粉样蛋白-β 清除的调节

• 批准号: 24770116
• 负责人: FUNAKOSHI Yuji
• 金额: $ 3万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24770116/
• 关键词: Arf6; PIP5K; βアミロイド; 細胞内輸送; Megalin; LRP1; アミロイドβ; 膜輸送; 低分子量G蛋白質Arf6; リン脂質キナーゼPIP5K

The plasma membrane receptors Megalin and LRP1, play a pivotal role in elimination of the Amyloid-beta peptide (Abeta), which is crucially involved in Alzheimer's disease, from the brain. In brain microvascular endothelial cells and choroid plexus epithelial cells, both receptors uptake Abeta from the brain fluid and transport them to the blood. In this research we find that the small GTPase Arf6 and the phospholipid kinase PIP5K bind to the cytoplasmic domains of Megalin and LRP1. We also demonstrate that knockdown of Arf6 causes accumulation of Megalin and LRP1 at intracellular endosomes and significant increase of the expression level of those proteins. These results indicate that Arf6 regulates transport of Megalin and LRP1 to lysosomes for degradation.

质膜受体Megalin和LRP1在大脑中消除淀粉样蛋白肽（Abeta）的过程中起着关键作用，而淀粉样蛋白肽是阿尔茨海默病的关键因素。在脑微血管内皮细胞和脉络膜丛上皮细胞中，两种受体都从脑液中摄取β并将其转运到血液中。本研究发现小GTPase Arf6和磷脂激酶PIP5K与Megalin和LRP1的细胞质结构域结合。我们还证明，敲低Arf6会导致Megalin和LRP1在细胞内核体的积累，并显著增加这些蛋白的表达水平。这些结果表明，Arf6调节meggalin和LRP1转运到溶酶体进行降解。

项目成果

Anti prolifetative protein Tob directly regulates c-myc proto-oncogene expression through cytoplasmic polyadenylation element-binding protein CPEB

抗增殖蛋白Tob通过胞质多腺苷酸化元件结合蛋白CPEB直接调控c-myc原癌基因表达

• 发表时间: 2012
• 作者: Ogami;K.;Hosoda;N.;Funakoshi;N.;Hoshino;S
• 通讯作者: S

Molecular mechanisms of fMLP-induced superoxide generation and degranulation in mouse neutrophils

fMLP 诱导小鼠中性粒细胞超氧化物生成和脱粒的分子机制

• DOI: 10.1016/j.jbior.2012.09.001
• 发表时间: 2013
• 期刊: Adv. Biol. Reg.
• 作者: Kanaho Y.;Sato T.;Hongu T.;Funakoshi Y.
• 通讯作者: Funakoshi Y.

Ubiquitin-specific protease TRE17/USP6 targets clathrin-independent cargo to recycling

泛素特异性蛋白酶 TRE17/USP6 以不依赖网格蛋白的货物为目标进行回收

• 发表时间: 2013
• 作者: Yuji Funakoshi;Yasunori Kanaho;Julie G. Donaldson
• 通讯作者: Julie G. Donaldson

Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

• DOI: 10.1128/mcb.00869-12
• 发表时间: 2013-01-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Sato, Takanobu;Hongu, Tsunaki;Kanaho, Yasunori
• 通讯作者: Kanaho, Yasunori

Ubiquitin-specific prtotease TRE17/USP6 targets clathrin-independent cargo to recycling

泛素特异性蛋白酶 TRE17/USP6 以不依赖网格蛋白的货物为目标进行回收

• 发表时间: 2012
• 作者: Funakoshi Y;Kanaho Y;Donalson JD
• 通讯作者: Donalson JD